Chroman-4-One Derivatives Targeting Pteridine Reductase 1 and Showing Anti-Parasitic Activity
by
Flavio Di Pisa 1, Giacomo Landi 1
, Lucia Dello Iacono 1, Cecilia Pozzi 1, Chiara Borsari 2, Stefania Ferrari 2, Matteo Santucci 2, Nuno Santarem 3, Anabela Cordeiro-da-Silva 3, Carolina B. Moraes 4, Laura M. Alcantara 4, Vanessa Fontana 4, Lucio H. Freitas-Junior 4,5, Sheraz Gul 6, Maria Kuzikov 6, Birte Behrens 6, Ina Pöhner 7, Rebecca C. Wade 7,8,9, Maria Paola Costi 2,* and Stefano Mangani 1,10,*
Flavio Di Pisa 1, Giacomo Landi 1, Lucia Dello Iacono 1, Cecilia Pozzi 1, Chiara Borsari 2, Stefania Ferrari 2, Matteo Santucci 2, Nuno Santarem 3, Anabela Cordeiro-da-Silva 3, Carolina B. Moraes 4, Laura M. Alcantara 4, Vanessa Fontana 4, Lucio H. Freitas-Junior 4,5, Sheraz Gul 6, Maria Kuzikov 6, Birte Behrens 6, Ina Pöhner 7, Rebecca C. Wade 7,8,9, Maria Paola Costi 2,* and Stefano Mangani 1,10,*
1
Department of Biotechnology, Chemistry and Pharmacy, University of Siena, 53100 Siena, Italy
2
Department of Life Sciences, University of Modena and Reggio Emilia, Via Campi 103, 41125 Modena, Italy
3
Institute for Molecular and Cell Biology, 4150-180 Porto, Portugal and Instituto de Investigação e Inovação em Saúde, Universidade do Porto and Institute for Molecular and Cell Biology, 4150-180 Porto, Portugal
4
Laboratório Nacional de Biociências (LNBio), Centro Nacional de Pesquisa em Energia e Materiais (CNPEM), Campinas SP13083-100, Brazil
5
GARDE, Instituto Butantan, São Paulo SP05503-900, Brazil
6
Fraunhofer Institute for Molecular Biology and Applied Ecology Screening Port, D-22525 Hamburg, Germany
7
Molecular and Cellular Modeling Group, Heidelberg Institute for Theoretical Studies, 69118 Heidelberg, Germany
8
Center for Molecular Biology (ZMBH), DKFZ-ZMBH Alliance, Heidelberg University, 69120 Heidelberg, Germany
9
Interdisciplinary Center for Scientific Computing (IWR), Heidelberg University, 69120 Heidelberg, Germany
10
Magnetic Resonance Center CERM, University of Florence, 50019 Sesto Fiorentino (FI), Italy
*
Authors to whom correspondence should be addressed.
Academic Editor: Thomas J. Schmidt
Molecules 2017, 22(3), 426; https://doi.org/10.3390/molecules22030426
Received: 7 February 2017 / Revised: 1 March 2017 / Accepted: 3 March 2017 / Published: 8 March 2017
(This article belongs to the Special Issue COST CM1307: Targeted Chemotherapy towards Diseases Caused by Endoparasites—Proceedings in Medicinal and Natural Product Chemistry)
Flavonoids have previously been identified as antiparasitic agents and pteridine reductase 1 (PTR1) inhibitors. Herein, we focus our attention on the chroman-4-one scaffold. Three chroman-4-one analogues (1–3) of previously published chromen-4-one derivatives were synthesized and biologically evaluated against parasitic enzymes (Trypanosoma brucei PTR1–TbPTR1 and Leishmania major–LmPTR1) and parasites (Trypanosoma brucei and Leishmania infantum). A crystal structure of TbPTR1 in complex with compound 1 and the first crystal structures of LmPTR1-flavanone complexes (compounds 1 and 3) were solved. The inhibitory activity of the chroman-4-one and chromen-4-one derivatives was explained by comparison of observed and predicted binding modes of the compounds. Compound 1 showed activity both against the targeted enzymes and the parasites with a selectivity index greater than 7 and a low toxicity. Our results provide a basis for further scaffold optimization and structure-based drug design aimed at the identification of potent anti-trypanosomatidic compounds targeting multiple PTR1 variants.
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Keywords:
pteridine reductase 1; Trypanosoma brucei; Leishmania spp.; chroman-4-one; chromen-4-one; crystallographic studies
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MDPI and ACS Style
Di Pisa, F.; Landi, G.; Dello Iacono, L.; Pozzi, C.; Borsari, C.; Ferrari, S.; Santucci, M.; Santarem, N.; Cordeiro-da-Silva, A.; Moraes, C.B.; Alcantara, L.M.; Fontana, V.; Freitas-Junior, L.H.; Gul, S.; Kuzikov, M.; Behrens, B.; Pöhner, I.; Wade, R.C.; Costi, M.P.; Mangani, S. Chroman-4-One Derivatives Targeting Pteridine Reductase 1 and Showing Anti-Parasitic Activity. Molecules 2017, 22, 426.
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